Mononuclear phagocytes comprise a pluripotential cell line with widely diverse properties. Circulating monocytes migrate into the tissues and then differentiate into macrophages, the properties of which depend on the local environment, which includes the presence of serum components. Such monocyte-derived macrophages represent a key component of the inflammatory cell infiltrate into tumors, and the tumoricidal activity of these macrophages is thought to play a major role in the rejection process. Serum surrounds monocytes in the circulation and activated serum components are found in lesions containing monocyte-derived macrophages. Therefore, we propose to examine serum substances which promote differentiation of human monocytes in extravascular tissues and in vitro. This will involve isolation of serum-derived inducer(s) of monocyte differentiation. Active fragments of the third and fifth components of complement will specifically be examined for their ability to induce differentiation. Monocyte differentiation will be assessed by measuring in vitro cytolysis of SV40-virus transformed human cells. After the inducer is isolated, its physical-chemical characteristics will be determined. Finally, the characteristics of the interaction of the inducer and monocytes will be examined. Preliminary studies of the interaction will include an examination of the effect of different concentrations of inducer on the kinetics of the appearance of "macrophage" functions, the possibility that the inducer acts on the cell by altering monocyte adherence, and that the duration of inducer-monocyte contact is important. By analyzing the induction of the differentiation process in vitro, we hope eventually to develop the means to modulate this process in vivo. This would make it possible to increase macrophage activity when that would be beneficial (i.e., in tumor rejection). This study will also characterize endogenous materials in serum which modulate monocyte maturation and are likely to be active in vivo.